RASP-UK - Moving away from the ‘one size fits all’ approach to treatment in severe asthma

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Scientific and Clinical Outcomes and Impact of the United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

Scientific and Clinical Outcomes and Impact

 

Validation of objective testing of corticosteroid exposure to identify non-adherence in difficult asthma - stratification based on non-adherence to inhaled corticosteroids 

 

A key aim of the Consortium was to validate objective testing of corticosteroid exposure to identify non-adherence in difficult asthma. Non-adherence to inhaled (ICS) and oral corticosteroid (OCS) therapy is a major clinical problem which is associated with worse asthma outcomes and increased healthcare costs but which is poorly detected by physicians and under-recognised and reported by patients . Non-adherence is clinically indistinguishable from steroid resistance and enrolment of non-adherent patients into clinical trials reduces statistical power and targets expensive new biological therapies inappropriately. We have developed a validated method for interpreting serum prednisolone and cortisol measurements (Using prednisolone and cortisol assays to assess adherence in oral corticosteroid dependant asthma: an analysis of test-retest repeatability), which is now used in routine care.

 

We have published a validated methodology aligning directly monitored ICS treatment with biological response, (Remotely Monitored Therapy and Nitric Oxide Suppression Identifies Nonadherence in Severe Asthma ) to distinguish non-adherence from ICS resistance (FeNO non-suppression Identifies corticosteroid-resistant Type 2 signalling in severe asthma and FeNO non-suppression identifies biological corticosteroid resistance). We have published data identifying who is non-adherent using this model of care, shown that adherence improves over time, and that the method is a useful  prediction tool to identify suitable (i.e. adherent) patients to progress to biologic therapy (Faruqi et al, Boddy et al and Butler et al). Identifying poor adherence should also facilitate a conversation between patient and clinician to explore and find solutions to improving adherence. This approach is advocated in the Global Initiative for Asthma International Guidelines and multiple National Asthma Guidelines, prior to initiating biologic therapies and was endorsed by an NHS England/Academy Medical Sciences Forum 2017 statement, and has been adopted in the NHS England Severe Asthma Toolkit. We have also partnered with GSK to deliver the first randomised controlled trial of the effect of a connected inhaler technology to improve medication adherence in uncontrolled asthmatic patients (GSK connected inhaler study ). The INCA-SUN study (INCA-SUN), which was a co-opted study to the RASP-UK programme, also demonstrated that Implementing evidence-based asthma management strategies using objective digital data on adherence, inhaler technique and lung function led to a significant favourable impact on treatment decisions (revisions submitted to Lancet Respiratory Medicine). This stratified approach combining adherence/biomarker profiling and adherence support in pre-biologic patients, has been implemented across UK severe asthma centres through an NHS Joint Working Agreement in partnership with Propeller Health & GSK, as a direct “pull-through” from RASP-UK adherence programme into routine clinical care.

 

Clinical trial optimising corticosteroid therapy using a composite T2 biomarker strategy

 

The primary analysis of this study (RASP-UK biomarker study), established the low prevalence of non-T2 mediated severe asthma, which has since been shown in other studies (Eosinophilic and non-eosinophilic Asthma - expert consensus framework). We also demonstrated improved outcome with biomarker-directed corticosteroid adjustment compared to current care, with reduced exacerbation rate and lower corticosteroid dose (primary outcome) in patients with uncontrolled severe asthma.

 

We have performed a series of secondary analyses of this trial, including outcome when stratified by biological sex (JACI in Practice in press), which demonstrated that females achieved greater benefit from biomarker-directed corticosteroid optimisation versus symptom-directed treatment (the current Guideline approach) compared to males. We also demonstrated that men and women report symptoms differently using the most commonly used validated instrument (Asthma Control Questionnaire – ACQ). Women generally have higher symptom scores in severe asthma, but when this is adjusted for body mass index and mood disorder, there is no sex difference. This observation suggests that women are more likely to have inappropriate treatment escalation using current asthma management guidelines and this should prompt a review of ACQ as a measure of asthma control in severe asthma in phase 3 studies of novel treatments in severe asthma.

 

We have also explored factors affecting why patients did not follow the treatment advice in this clinical trial of patients with severe asthma (Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma), which challenges the recommended ‘step-down’ treatment model embedded in Asthma Management Guidelines. We have also used a novel clinical trial analysis methodology (Per protocol analysis in clinical trials ) to produce a true estimate of the efficacy of biomarker-directed corticosteroid treatment adjustment in patients with severe asthma (Bannon et al. Addressing non-adherence to clinical trial interventions: per protocol‑ analysis of randomised control trial data using g-computation – European Respiratory Journal under review). 

 

In collaboration with Amgen, we have generated novel whole blood transcriptomic data in severe asthma and shown that, after controlling for OCS therapy, there are distinct signatures seen in patients with evidence of elevated T2-biomakers, however most significantly, no such transcriptomic signatures associated with T2 biomarker-low participants.  (Transcriptomic signature in type-2 biomarker low severe asthma: relationship with asthma control – Journal of Allergy and Clinical Immunology – manuscript under review). This data is consistent with multiple negative trials of therapies targeting putative non-T2 pathways including interleukin-17, interleukin-23 and tumour necrosis factor-alpha in uncontrolled asthma.

 

In parallel, with the Karolinska Institute, we have analysed urinary eicosanoids in the biomarker study and have demonstrated different urinary eicosanoid profiles in T2-biomarker low subjects, which we are currently exploring further (manuscript currently being drafted). We are extending this work and performing urinary metabolomics in collaboration with the Karolinska with data available in early 2024. 

 

Exacerbation profile in non-T2 severe asthma

 

We have also published novel data on the inflammatory profile and clinical risk factors for T2‑biomarker low ( T2LOW) exacerbations in severe asthma, which was an important secondary aim in the biomarker study (Exacerbation Profile in Type-2–Low Severe Asthma). This study confirmed that asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlighted the important unmet need in this patient population and the necessity to delineate further mechanisms in non-T2 driven exacerbation events. This observation is supported by data in our bronchoscopy study where persisting pathological changes are seen, which are independent of T2-cytokine driven eosinophilic inflammation. (See below)

 

We also studied exacerbations in subjects on biologic therapy (mepolizumab – the MEX study) and demonstrated that exacerbations on mepolizumab are two distinct entities: non-eosinophilic events, which are driven by infection with a low FeNO and high C-reactive protein and eosinophilic exacerbations that are FeNO high. Of clinical importance, these events can largely be differentiated using a simple non-invasive test (FeNO) and will allow better treatment choices by preventing inappropriate switching of biologic therapy and appropriate targeting of bacterial infection. The results of the MEX study challenge the routine use of OCS for the treatment of all asthma exacerbation events, particularly in this population and UK clinicians are currently using this data to better target OCS in patients on biologic therapy (verbal communication from UK Severe Asthma Network and Registry). This better targeting of OCS in exacerbations is particularly relevant to one of our patient defined goals in the programme.

 

In further support of the critical role of infection in T2-low exacerbation events, we have performed detailed microbiome analyses of the biomarker and MEX studies (RASP-UK microbiome study) and demonstrated that in T2-biomarker high patients, a high FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We also demonstrated that mepolizumab does not alter airway microbial composition.

 

As part of our aim was to generate data on targeting OCS better, the Consortium also performed a randomised, triple-blind, placebo-controlled crossover trial of prednisolone in adults with severe eosinophilic asthma established on mepolizumab (MAPLE study). Although, this study demonstrated some improvement in small-airway obstruction (measured by oscillometry) and reduced residual biomarkers of type 2 inflammation (FeNO and sputum eosinophils), there was no significant effect on asthma symptoms or quality of life.

 

Consistent with our plan to try and better understand exacerbation events and potentially reduce OCS use, we are performing the BENREX study (BENREX). This is a phase IV, open-label, prospective, multi-centre study in patients with severe eosinophilic asthma, treated with Benralizumab (anti-IL5 receptor antibody). The exploratory study will assess deteriorations in asthma control (exacerbations) to characterise the clinical severity and the airway and systemic inflammatory phenotype associated with these events - 150 participants will be recruited and receive treatment for at least 56 weeks (currently 137 in the study) and study will finish in February 2024. This study was delayed substantially due to the pandemic requiring substantial protocol modification, which we utilised as an opportunity to adjust the protocol for the pandemic using digital and remote monitoring technologies (Adapting BenRex Study Design)

 

Investigate the airway transcriptome and microbiome in bronchoscopic samples

 

We have published the immunohistology data from the RASP-UK bronchoscopic study (RASP-UK bronchoscopy immunohistology), which has demonstrated suppressed airway mucosal eosinophilic inflammation in both T2-high and T2-low asthma, but persistent T2 cytokine production in T2-high asthma compared to T2-low asthma. Both T2-high and T2-low asthma demonstrate persistent remodelling, namely increased airway smooth muscle mass, increased glandular mass, and increased mucus (MUC5AC) production, when compared to healthy controls. These data suggest (i) that local exposure to ICS is having an impact on tissue eosinophils, which are highly sensitive to steroids, but may not suppress cells that produce T2 cytokines such as ILC2 cells and mast cells, ii) that as eosinophil-targeted biologics work most effectively in those with high T2-biomarkers, it is systemic eosinophils that drive eosinophilic asthma exacerbations rather than resident tissue eosinophils, and iii) as airway remodelling changes (increased ASM mass, glandular hyperplasia and excess mucus production) persist in both severe T2 biomarker-high and T2 biomarker-low asthma, these are responsible for residual disease expression beyond eosinophilic inflammation. Considering that bronchoconstriction and mucus plugging are predominant causes of airflow obstruction driving asthma symptoms, exacerbations and death, the factors that sustain these abnormal pathological features should be a priority for future research and drug development. The transcriptomic data will provide further mechanistic insight, but there has been a substantial delay caused by challenges with processing and analysing this data at Genentech as originally planned (see 3c legacy).

 

Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA)

 

Further analysis by splitting the cohort into a training and a test set with application of Random Forest analysis to the dataset has generated results which are more definitive and, therefore, more relevant to clinical practice. Predictive biomarkers of response were examined including volatile organic compounds (VOCs), measured by GC-MS, and a set of plasma lipids. Crucially, both these platforms performed well as predictive biomarkers, with ROC AUCs for both was greater than 0.7 (manuscript under preparation for Journal of the American Medical Association). One of the emergent challenges in choosing omalizumab as a biologic choice in severe asthma has been the lack of predictive biomarkers of therapeutic response which are available for the newer biologic therapies. Validation of a predictive biomarker would have major impact for patients in improving the ability to identify those suitable for omalizumab.

 

Scientific Insights

 

Our published methodology aligning directly monitored ICS treatment with biological response, has produced a novel model of ICS resistance (FeNO non-suppression Identifies corticosteroid-resistant Type 2 signalling in severe asthma and FeNO non-suppression identifies biological corticosteroid resistance). Previous work in CS resistance has been flawed as confirmation of treatment exposure was uncertain and future work will use this model to study mechanisms in ICS resistance. Pharma is now engaging with RASP-UK to use this model in Phase 2a ‘proof of concept’ studies to explore available putative therapies to ‘unlock’ this ICS resistance (e.g. inhaled JAK inhibitors)

 

Our pivotal biomarker clinical trial to optimise CS treatment provided important novel insights into challenges with the delivery of the standard guideline based approach, which escalates treatment with to gain asthma symptom control followed by reduction when control is achieved. We demonstrated that adherence to this model of care by patients was poor with substantial variation across clinical sites. We partnered with GSK, who in parallel published a clinical trial supporting better outcomes with targeted treatment escalation (Captain study), and RASP-UK Biomarker study co-leads (Heaney and Pavord), along with other international leaders, proposed an alternative for delivery of precision care in asthma (Where next for Asthma Guidelines?).

 

Although the ITT analysis was negative in our primary biomarker study, due to poor patient adherence with the treatment advice, this was noted to be an issue at some sites only. These were clinical sites where biomarker directed treatment decisions are not used in routine care and would suggest that patient engagement and adherence with biomarker directed treatment advice can be substantially improved. In keeping with this, we have now performed a secondary analysis using g-computation to model the outcome if adherence was consistent across clinical sites. This is important because our ITT analysis does not address the patient-centred question, specifically “What will this treatment do for me (i.e. efficacy) when I take it?” This further analysis has shown clearly that there are significant clinical benefits in using biomarker based down-titration of CS treatment in severe asthma, and using this analysis, we plan to advance the use of this clinical strategy with the clinical leads of International Asthma Management Guidelines.

 

The MEX study (MEX study) demonstrated persistent eosinophilic airways inflammation in patients on anti-IL5 treatment (mepolizumab). In a further analysis, supported by additional funding from GSK, we have performed proteomic analysis (1156 proteins measured in sputum – O‑link Proximity Extension Assay. Unsupervised classification identified a distinct cluster of patients with a long disease duration, characterised by persistent eosinophilic airway inflammation and a population of airway eosinophils which are not IL-5 dependent. This persistent eosinophilic inflammation was characterised by increased IL-1 and IL-6 related proteins and notably, this distinction was evident pre-Mepolizumab and was associated with significantly longer disease duration (manuscript in preparation). This intriguing finding suggests differentially regulated populations of eosinophils in the airway which may reflect a compensatory mechanism to prolonged CS exposure in severe asthma, which we are currently exploring further using our biobanked samples in MEX and the biomarker study.

 

The key findings to-date from the bronchoscopy study are that T2 biomarker-high CS-insensitive patients had elevated airway T2-cytokines (IL-4/-5), chemokines (CCL17/-26), alarmins (IL-33, TSLP), and eosinophils in sputum, and a high T2-dependent gene signature. T2-high patients also had a lower IL-17-dependent gene signature in keeping with previous studies. Gene Set Enrichment Analysis suggests several distinct previously unidentified pathways are up/downregulated in T2-high and T2-low asthma – this is the subject of ongoing analysis. To our surprise, we found similar eosinophil, neutrophil and mast cell tissue numbers across severe asthma and health. By contrast remodelling features (ASM mass, MUCAC expression) were increased across all asthma phenotypes, and lipid mediators (PGD2 and LTE4) were similar across the asthma groups suggesting ongoing mast cell activation. Thus airway remodelling and mast cell activation are evident in both T2-high and T2-low severe asthma, and are likely important for residual disease expression beyond eosinophilic exacerbations, and an important area for further study. 

 

The SOMOSA study has demonstrated that novel biomarkers (VOCs measured by GC-MS) and a set of plasma lipids perform well as predictive biomarkers for response to omalizumab, which may translate into clinical practice.

 

In summary, the series of publications and ongoing work from the RASP-UK programme have reframed many important clinical questions in both clinical management and mechanistic insights in severe asthma and have set the scene for the next series of studies to address these questions.

 

RASP UK Legacy

 

The RASP-UK legacy Committee has been established to ensure that all data and samples from the RASP-UK programme will continue to serve a scientifically and ethically just purpose, including managing requests from external sources outside of the RASP-UK programme for the use of the RASP-UK trial data and/or samples stored for future ethically approved research.

 

The clinical and omics data sets of RASP-UK have been successfully uploaded to the tranSMART platform, which platform enables real-time analyses. It has been aligned with the UBIOPRED and SOMOSA datasets and ensures accessibility, sustainability and transparency of data which is essential for future respiratory projects within the EU and the UK. Requests for accessing the RASP-UK data management platform will be managed by the RASP-UK Legacy Committee.

 

The first request for access to data and samples has been approved using data and bronchial biopsy samples in a project entitled ‘High resolution spatial analyses of pathology in airway tissues in the MRC RASP-UK severe asthma cohort’. The study will apply novel, high-resolution, spatial transcriptomics, proteomics, lipidomics and epigenomics to bronchial biopsy samples from are unique cohort of highly-phenotyped treatment-optimised people with severe asthma. For the first time this will enable elucidation of underlying mechanisms of airway inflammation and tissue remodelling in severe asthma that cannot be obtained from bulk tissue analyses. Thus it will be possible to study the role of alarmins from airway epithelial cells and of type-2 cytokines, chemokines and eicosanoid mediators from specific inflammatory cells within the airway mucosa in ICS resistance; and identify differences in the airway smooth muscle and epithelial transcriptome, proteome, and epigenome in T2-biomarker high and low asthma that support ongoing airway smooth muscle dysfunction driving bronchoconstriction and airway hyper-responsiveness, and the goblet cell hyperplasia that drives excess mucus secretion, irrespective of the cytokine environment. This project is being undertaken through a collaboration involving the Universities of Leicester, Oxford and Nottingham, and is the subject of a current application to the MRC PSMB.

 

As discussed above, processing the bronchoscopic transcriptomic data (bronchial brushings and biopsies) has been significantly delayed but the data has now been received by the RASP-UK team. It is currently being analysed by the bioinformatics team at University of Oxford (Dr Tim Hinks and Emanuele Marchi, Nuffield Department of Medicine, University of Oxford) and should be available in the coming 2 months. Whilst we were disappointed with the delay in data processing and access, this has been mitigated by bringing new and younger members into the RASP-UK Consortium to ensure that the data is advanced but additionally to ensure ongoing collaborative working as part of the RASP-UK legacy.

 

RASP-UK has established a future collaboration with Amgen/deCODE (deCODE ) which will perform detailed proteomic analysis on the biosamples from the biomarker study and analyse these with the genomic and transcriptomic data using their established methodology (Large-scale integration of the plasma proteome with genetics and disease | Nature Genetics) with a number of specific aims: Aim 1: Identification of plasma protein markers associated with systemic corticosteroid exposure; Aim 2:  Identification of plasma protein markers associated with severe asthma endotypes; Aim 3: Identify protein associations with T2-low exacerbations and Aim 4: Identify genetic variants associating with asthma endotypes - this will combine RASP-UK data with other datasets available at deCODE, including genomic and proteomic data already available on Icelandic subjects and participants in UK biobank.

 

We have established a new collaboration with partners at the University of Nottingham (Ian Sayers and Katherine Fawcett) and have appointed a new PhD student (Matt Saward - Wellcome Trust Doctoral Training Programme in Genomic Epidemiology and Public Health Genomics) to analyse the results of the blood DNA samples within a wider programme of work in T2 ‑biomarker-low severe asthma with the hypothesis being that asthma risk signals drive specific clinical and pathological aspects of asthma. We are currently working with a new Industry Partner, 23andMe, to facilitate a genotyping study in the UK Severe Asthma Registry, in the clinical centres in the RASP-UK Consortium, which will be performed as part of this programme. We recognise that the prevalence of a “pure” T2 low severe asthma phenotype is low, but what is very common is a group who have persistent symptoms despite suppression of T2 signals and eosinophilic inflammation and who have treatment escalated due to these non-T2 mechanisms. We will also explore the relationship between moderate-severe asthma genetic risk scores and phenotypes. 

 

The results of the MEX study (MEX study) have challenged the routine use of OCS for the treatment of all asthma exacerbation events, particularly in patients on biologic therapy. Clinicians in the UK are currently using this data to better target OCS and advanced discussions are ongoing in the UK to submit a grant application across the RASP-UK centres for a controlled (prednisolone v placebo) in biomarker low subjects on biologic therapy. 

 

In collaboration with Amgen, and following on from our initial analysis using novel whole blood transcriptomic data in the biomarker study, we are currently analysing the whole blood transcriptome in exacerbation events in T2-high and T2-low exacerbation events in this study. This will explore dynamic changes from stable state to exacerbation event in individual patients, looking particularly for mechanistic signals in patients with T2-low exacerbations. 

 

Consistent with our plan to try and better understand exacerbation events and potentially reduce OCS use in patients with severe asthma on biologic therapy, the BENREX study (BENREX) will finish in February 2024. There is significant interest at the minute in the concept of clinical remission in severe asthma with biologic therapy (Expert consensus framework for asthma remission as a treatment goal ) and AstraZeneca have provisionally agreed to long-term follow-up of this patient cohort to determine how many achieve clinical remission and how many maintain this over a sustained period of time (estimated to extend to 2027 – contract being finalised). This data will provide additional data on the reasons for failure to achieve remission in this well characterised cohort with precise clinical and biomarker phenotyping.

 

The SOMOSA legacy Committee has also been established, again to ensure that all data and samples from the SOMOSA study programme will continue to serve a scientifically and ethically just purpose, including managing data requests and/or access to samples stored for future ethically approved research. The SOMOSA Legacy Committee have approved collaboration with 3TR (3TR EU project) to allow use of whole blood samples from SoMOSA have been transferred to Barcelona for transcriptomic analysis as part of the 3TR consortium programme and anticipate the results will be available early in 2023. The Legacy Committee has also approved a collaboration with Dr Jessica Lasky-Su from the Brigham and Women’s Hospital, Harvard University (MTA signed) and expect to send them urine and plasma samples by December 2022 for metabolomic analysis. This will further characterise predictive biomarkers of response to omalizumab, but in addition, will allow specific mechanistic questions on the mode of action of omalizumab to be explored. 

 

Overall, RASP-UK, which initially leveraged the UK Severe Asthma Registry Network as the clinical infrastructure to deliver the programme, and in parallel with NHS Specialist Commissioning of Severe Asthma Services has had a substantial impact leading to the establishment of a sustainable clinical and research infrastructure for severe asthma in the UK. Much of the learning has been pulled through to other National Consortia e.g. NIHR EME funded BEAT-Severe Asthma, where the RASP-UK clinical sites and investigators are again working together to deliver a pivotal national research programme in severe asthma.

 

Throughout the RASP-UK programme, the Consortium has fostered conversations among the severe asthma clinical community, around the novel insights from the programme, using our strategy of promoting findings published in the scientific literature - press releases, Twitter discussions and social media activities. The success of these efforts can be found in the altimetric scoring of our publications.

 

RASP UK and Industry Engagement

 

The RASP-UK programme has worked with multiple Pharma partners in the development and delivery of the research programme. In the legacy section, we have described examples of where there is ongoing interaction with Industry based on the RASP-UK programme, and where new opportunities have emerged with these partners. Substantial Industry engagement occurred during the writing, delivery and expansion of the Consortium and achieving the Consortium goals.

 

We would highlight the following Industry engagement with Pharma with the Consortium and proposed areas for ongoing engagement based on the programme findings:

 

  1. Additional resources from two new consortium members (GlaxoSmithKline and Boehringer Ingelheim who became partners in the Consortium in 2017) and total and in cash and in in kind contribution from Industry of £9,164,715 GBP at the end of the consortium.
  2. Ongoing development of the concept of clinical remission and particularly the concept of “incomplete remission” using currently available anti‑T2 therapies – this will mean the need for combination therapeutic approaches, as well as better biomarkers to define sub‑types of severe asthma. In line with this, AstraZeneca has provisionally agreed to long-term follow-up of the BENREX patient cohort to determine how many achieve clinical remission with Benralizumab [an eosinophil depleting antibody] and how many maintain this over a sustained period of time (estimated to extend to 2027 – contract being finalised) - we will biobank samples prospectively in this cohort to explore biological mechanisms in patients who fail to achieve clinical remission
  3. Quantifying residual disease and potential alternative mechanisms outside T2‑inflammation – we are currently working with industry partners to take this up, with proposed mechanisms including ongoing mast cell activation, earlier intervention with biologic therapies (for example to avoid development of fixed airflow obstruction) and persistent eosinophil activation despite anti-IL5 therapy with mepolizumab.
  4. Importance for airway sampling and particularly characterisation of exacerbations at the time of the event – this is an important area where there is very limited investment by industry in characterising exacerbation events, so this is a potential area for us to work with an industry partner – most Phase 3 studies in severe asthma are placebo controlled exacerbation studies but these events are defined by exposure to systemic corticosteroids – the MEX trial has shown that in many cases, this is probably delivering no benefit - we believe this approach would improve trial design if we could annotate events by mechanism or driving factor 
  5. Failure for symptom score methodology to account for gender differences, specifically how the ACQ performs differently in women with severe asthma
  6. Failure of current treatment paradigm of stepping up treatment in a ‘one size fits all’ approach – this assumes all symptoms are due to asthma, and will be corticosteroid responsive, which is incorrect. 
  7. Need for predictive biomarkers of treatment response earlier in development programme (Somosa/ omalizumab).
  8. Potential for individualised ICS needs – monitored ICS therapy and better definition of ICS resistance.
  9. The concept of “splitting” T2-low/T2 high disease based on biomarker thresholds is flawed as these biomarkers are substantially affected by background treatment, partially corticosteroids – this would be better replaced with a system of identifying underlying genetic risk and biology and optimised delivery of therapy rather than the current progressive ‘step-wise / one-size fits all’ escalation of treatment – this mandates a fundamental shift in our approach to treatment escalation and opens up the need for investment in biomarker measurement much earlier in the patient journey to prevent patient harm by inappropriate corticosteroid treatment – currently systemic steroids are given for high symptoms without evidence of airway inflammation and more work will be needed to discover the biology and disease trajectory underlying this symptom-high / T2‑ low group – Industry is not very aware or specifically engaged in this area
  10. Amgen/deCODE collaboration - RASP-UK has established a future collaboration with Amgen/deCODE (deCODE) which will perform detailed proteomic analysis on the bio-samples from the biomarker study ]
  11. GSK collaboration - our stratified approach combining adherence / biomarker profiling and adherence support programme in pre-biologic patients, has been implemented across UK severe asthma centres through an NHS Joint Working Agreement in partnership with Propeller Health and GSK
  12. Current confidential discussion to collaborate with 23andMe to deliver a genotyping study in the UK Severe Asthma Registry.

 

At a fundamental level Industry were looking for evidence of the biological mechanisms and clinical tractability of the severe asthma population that have an unmet need beyond T2 high biomarker defined asthma. We discovered through work-strand one that our original hypothesis that biomarker feedback can likely stratify the severe asthma T2-low enriched population, but there are issues involved in patient acceptance and methodology. Patients really do not buy into a model that titrates treatment over a bi-monthly basis and reducing treatment in the context of on-going symptoms is unacceptable for the majority. We learned that existing treatments do not fully manage airway inflammation and so some Industry participants are able to glean that there is still much work to be done to link genetics and biology to reveal a next generation of airway inflammation treatments. Other industry partners have been able to get a better understanding of the unmet need and can decide to engage or walk away with a particular therapeutic strategy. The overall effort has sustained the severe asthma sites that have contributed deep phenotyping of patients and have provided a bridge to build the scale that is needed to apply the next generation technology to dissect the presentation of severe asthma, specifically genomics.

 

Our results can maintain engagement in research for unmet needs in severe asthma. Industry efforts are split across target discovery, proof of concept early development and late stage development. RASP-UK has supported all the areas of industry effort. We have established and quantified the areas of unmet need and the ability to go after a group that are not well served by T2 treatments. We have quantified residual disease expression and the potential to improve on existing treatments while still directing existing treatments to the right people. We have shown the limitations of symptom measurement and the dire need to improve symptom measurement in clinical trials (ACQ failure issue/ gender differences). 

 

The discovery of glandular hyperplasia and excess mucus production that persist in both severe T2 biomarker-high and T2 biomarker-low asthma is a major finding that will provide impetus into an area that might be perceived by many as lacking in unmet need. The ability to measure residual disease expression beyond eosinophilic exacerbations is critical for industry to design clinical trials that are better able to demonstrate efficacy and confirm clinical utility. Considering that bronchoconstriction and mucus plugging are the predominant causes of airflow obstruction driving asthma symptoms, exacerbations and death, the factors that sustain these abnormal pathological features should be a priority for future research and drug development.

 

Industry is now able to prioritise the development of novel therapeutic development based on the understandings that have directly come from RASP-UK. Novel tools to quantify symptoms and adjust for gender differences in reporting are now able to be prioritised. 

 

The anti-IL33 therapies, while showing proof of concept in phase 2 in studies enriched for T2-low asthma have not progressed into phase 3 confirmatory trials. RASP-UK data and evidence is now able to design and justify Phase 3 confirmatory trials. 

 

We will continue to explore opportunities going forward, however one issue that has emerged is that when the ‘Consortium Agreement’ has terminated, there is no contractual framework or mechanism for Pharma to engage contractually with the wider Consortium, and effectively, additional interaction is with the Lead Institution e.g. the Amgen/deCode contract is with Queens University Belfast.